| Site | Grade I recommendations | Grade II recommendations | Grade III recommendations |
|---|---|---|---|
| Para‐aortic lymph node (no.16a2/b1) metastasis | Refer to the treatment of recurrent and metastatic gastric cancer or encourage participation in clinical trials | Neoadjuvant chemotherapy combined with radical gastrectomy a (Evidence 2B) | Radical surgery combined with chemoradiotherapy (Evidence 3) |
| Single liver metastasis b , c , d | Sequential systemic chemotherapy and surgery for the primary and metastatic tumors b (Evidence 2A) | Systemic chemotherapy combined with local treatment c (Evidence 2B) | |
| Ovarian metastasis | Surgery for the primary and metastatic tumor combined with systemic chemotherapyd,f (Evidence 2B) |
Notes
Prophylactic dissection of the para‐aortic lymph nodes in gastric cancer was not found to be beneficial in the JCOG9501 study [231]. In the REGATTA study [232], subgroup analysis of the para‐aortic lymph node (no. 16a2/b1) metastasis showed that surgery combined with chemotherapy was associated with a good curative effect. At present, the main mode of treating para‐aortic lymph node metastasis is neoadjuvant chemotherapy followed by sequential surgery. In the JCOG0001 study [233], it was reported that 2‐3 cycles of sequential chemotherapy with irinotecan and cisplatin before surgery were associated with a clinical effective rate of 56%, R0 resection rate of 65%, and 3‐year survival rate of 27%. However, because of the high death rate in the study, it was terminated early. The JCOG0405 study [234] reported that 2 cycles of neoadjuvant chemotherapy with S‐1 and cisplatin followed by D2 gastrectomy with para‐aortic lymph node dissection for gastric cancer with extensive lymph node metastasis was associated with a curative rate of 64.7%, R0 resection rate of 82%, and 3‐year OS of 58.8%. In the JCOG1002 study [235], docetaxel was added to the S‐1 combined with the cisplatin regimen of the JCOG0405 study (DCS regimen) and the observed clinical remission rate was found to be 57.7%, R0 resection rate 84.6%, and pathological remission rate was 50.0%, suggesting that the addition of docetaxel did not increase treatment efficacy. S‐1 combined with cisplatin is still considered the first choice for these patients [236]. A prospective study from the Zhongshan Hospital Affiliated to Fudan University showed that the overall PFS of gastric cancer patients with isolated para‐aortic lymph node metastasis after neoadjuvant chemotherapy combined with radical surgery was 18.1 months [237].
Synchronous liver metastasis of gastric cancer refers to the liver metastasis occurring 6 months before, during or 6 months after surgery [238]. Single liver distant metastasis refers to single hepatic metastasis of diameter ≤5 cm, and the metastasis is limited to one lobe without involvement of blood vessels and bile ducts. Currently, there is a lack of prospective randomized controlled clinical study data for the treatment of such patients. Results from the REGATTA study showed that palliative surgery only for primary lesion was not associated with survival benefit [232]. A retrospective study showed that selective gastric cancer patients with liver metastasis, i.e., including those aged <65 years old, with normal carcinoembryonic antigen (CEA) and cancer antigen 199 (CA199) levels at the time of diagnosis and non‐EGJ cancer, could obtain survival benefits through sequential chemotherapy and surgery [239]. Findings from a meta‐analysis showed that the prognosis of patients whose liver metastasis was resected was significantly better than non‐resected ones (mOS, 23.7 vs. 7.6 months) [240]. A systematic review showed that the 1‐, 2‐, 3‐, and 5‐year OS rates of patients who underwent gastrectomy plus hepatectomy were significantly higher than those with gastrectomy alone [241]. A systematic review of 39 retrospective studies found that resection of liver metastases could significantly improve prognosis (HR: 0.50; P < 0.001), especially in Far Eastern compared with Western studies, and patients with solitary liver metastasis [242]. A meta‐analysis found that relatively early T and N stage, no vascular invasion, maximum diameter of liver metastases <5 cm, negative margin, normal preoperative CEA and CA199 levels were important factors for better prognosis in gastric cancer patients with liver metastases who underwent systemic chemotherapy followed by surgery [243]. Findings from an EORTC and JCOG questionnaire survey [244], conducted in 2017 in 17 European countries and 55 research centers in Japan on gastric cancer patients with liver metastases whose primary and metastatic foci could be resected found that most centers recommend preoperative chemotherapy followed by resection of the primary and metastatic foci.
For patients with solitary liver distant metastasis not suitable for surgery, systematic chemotherapy combined with other local treatments, including radiofrequency ablation (RFA) [245], microwave ablation (MWA) [246], hepatic artery infusion chemotherapy (HAIC) [247, 248], transarterial chemoembolization (TACE) [249] and stereotactic body radiotherapy (SBRT) [250], can be considered. A retrospective multicenter study from Japan found no significant difference in the survival between patients who underwent surgical resection and those who underwent local treatment but also observed that patients staged as N0/N1 after the resection of their single metastatic and primary lesion had significantly better benefit from surgery or local treatment [251]. The results of a meta‐analysis showed that compared with systemic chemotherapy, systemic chemotherapy combined with RFA in patients with liver metastasis (diameter <3 cm) could significantly prolong the survival time of these patients, with an mOS of 22.93 months [252].
Krukenberg tumors are metastatic lesions of gastric cancer that have metastasized to the ovary. Systematic chemotherapy is still the main treatment for these patients. However, some retrospective studies have shown that systematic chemotherapy combined with surgical resection of the primary tumor and/or ovarian metastasis could provide some survival benefits to these patients by increasing their median survival from 6‐9 months to 19‐23.7 months [253]. The most determining prognostic factors of these patients were an ECOG PS of 0‐1, R0 resection (radical resection of the primary lesion and the ovarian metastatic lesion), and postoperative systemic chemotherapy [254], while signet ring cell pathology and peritoneal metastasis were the poor prognostic factors [255]. For patients with single distant ovarian metastasis, only some highly selected patients were found to benefit from surgery combined with systemic chemotherapy. However, there is no definite consensus regarding the selection of patients, timing of treatments, and methods for such operations.